The overall goal of this Program Project is to understand how the ets gene family functions in the regulation of cellular growth, differentiation and transformation. Family members play an important role in hematopoiesis, angiogenesis and vascular development. That the ets genes have a role in cancer was first suggested by the presence of ets sequences found in the oncogenic virus, E26. Family members are located in chromosomal regions associated with certain leukemias, Down Syndrome and retroviral induced cancers. The ets genes are transcriptional factors, have independent activities and are likely to constitute a fundamental integrated regulatory network. The precise interplay among the members of this network has not as yet been elucidated. Although considerable work has been done the individual family members, no coherent efforts have been made to fully understand the functional inter-relationships among the family members. This Program Project proposes to study the interplay among these genes, and the key questions to be addressed are, 1) why do the ets genes occur as a family? What are the functional redundancies among the family members? ii) what other regulatory proteins interact with each family member? Does each ets gene family member interact with unique or common proteins? iii) What are the target genes for each family member? Are these target genes regulated by single or multiple members of the ets family? iv) In what signal transduction pathway are the ets genes family members involved? v) What are the roles of ets family members in oncogenesis, tumor suppressor and aberrant development? This Program Project focuses on studies of ETS1 and FLI1 cloned and characterized extensively studied by the principal Investigator and his collaborating PI's. These genes are representatives of the entire ets gene family, and their study will expand our knowledge of the function of the entire family.